Velocardiofacial syndrome (VCFS), also known as 22q11.2 deletion syndrome, is associated with congenital anomalies, neurocognitive deficits, and, in up to 30 percent of adults with this syndrome, schizophrenia (SZ). In this competitive renewal application, we are proposing to continue our longitudinal study of biomarkers for psychosis in VCFS that we began in 2002. During the 2007-2011 funding cycle, we have begun to map the trajectory of cognitive, psychiatric and neuroanatomic development in children with VCFS, and to determine which of these factors predict prodromal symptoms of psychosis. Data from this funding cycle have revealed that within the developmental window of mid-adolescence in youth with VCFS, the most robust predictors to prodromal symptoms of psychosis were longitudinal cognitive decrements in verbal learning, visual working memory and executive function, and neuroanatomic decrements in the volumes of prefrontal cortex, temporal lobe gray matter and hippocampus. However, the youth in our sample are just reaching the age at which they are most vulnerable to the onset of SZ. Accordingly, it is critical that we continue follow ths cohort in order to identify the factors that are associated with, and may be predictive of, the onset of SZ. The goal of the proposed project is to extend our investigation of this large sample through a fourth phase of data collection, which will span the age range (18 - 24 years) during which youth with VCFS are at the highest risk of developing SZ. Based on our findings from the current funding cycle, and the knowledge that in non-VCFS individuals, rapid myelination of frontal and temporal lobes is occurring at a time when symptoms of SZ are beginning to appear, we propose to apply diffusion tensor imaging to investigate the integrity of the white matter tracts in VCFS at this timepoint. Accordingly, we propose to take this project in a new, innovative direction by applying state-of-the-art methods to investigate the extent to which anomalies in microstructural white matter in VCFS are associated with vulnerability to severe psychiatric illness. Our specific aims are: 1) to continue to investigate the trajectory (across Timepoints 1, 2, and 3) of frontal and temporal lobe regions of interest on the development of psychosis at Time 4; 2) to investigate the integrity of fronto-temporal, fronto-parieto-occipital, and corona radiata fiber bundles in VCFS; 3) to investigate the association between structural connectivity in fronto-temporal and fronto-parieto-occipital tracts and cognitive, social and regulatory processes that comprise functional deficits in psychotic illness (utilizing constructs from the NIMH Research Domain Criteria Project); 4) to investigate the effect of allelic variation in ten functional single nucleotide polymorphisms (SNP's) of seven Candidate genes at the 22q11.2 locus on alterations in fronto-temporal and fronto-parieto-occipital white matter pathways; and 5) to develop useful predictors of psychosis for VCFS youth. The knowledge we gain from this study will move the field forward by elucidating and specifying the neurobiological basis of vulnerability to SZ in VCFS, thus paving the way for early identification and treatment of youth at highest risk for psychosis. PUBLIC HEALTH RELEVANCE: Up to 30 percent of adults with the genetic disorder, velo-cardio-facial syndrome (VCFS; also known as 22q11.2 deletion syndrome) develop schizophrenia. The continuation of our longitudinal study of biomarkers for psychosis in VCFS, in which we will investigate neuroanatomic alterations with anatomic magnetic resonance imaging and diffusion tensor imaging, will permit us to elucidate the neurobiological basis of vulnerability to psychosis in youth with this genetic disorder. The high rate of schizophrenia in VCFS constitutes a significant public health concern for both families and society. Identifying those neurobiological factors that place youth with VCFS at the highest risk for schizophrenia will impact positively on the early, preventative intervention and treatment of psychiatrically impaired children and youth with VCFS, thus reducing its toll on families and society.